Black is white, up is down and short is long,
And everything you thought was just so
important doesn't matter
Everything you know is wrong,
Just forget the words and sing along,
All you need to understand is
Everything you know is wrong
- Wierd Al Yankovic

Wednesday, January 18, 2012

How Cancer Drugs Make Cancer Worse and Kill Patients (Updated)

You'd think that a tumor shrinking would be considered good news for anyone suffering from cancer. But maybe not. Scientists have found that a type of cancer treatment aimed at shrinking tumors can actually make them spread more efficiently and kill patients quicker.

Choking off tumors' blood supply with an approach called anti-angiogenesis, is the mechanism of many cancer drugs. But a new study says it might have the frightening side effect of causing tumors to metastasize aggressively.

Anti-antiogenesis is the fundamental function behind many widely-used cancer drugs. For the study, the researchers looked at imatanib (brand name Gleevec), a leukemia drug and sunitinib, (brand nameSutent), a treatment for gastrointestinal tumors.

I spoke to Dr. Raghu Kalluri, one of the study's authors and chief of the matrix biology division at Beth Israel Deaconess Medical Center in Boston. He said focusing on tumor growth, the treatment results looked good. Tumors shrunk. But if you looked at the big picture, making tumors smaller didn't mean the cancer was being controlled. It was actually spreading.

"Whatever manipulations we're doing to tumors can inadvertently do something to increase the tumor numbers to become more metastatic, which is what kills patients at the end of the day," Kalluri said.

The paper was published in the January 17 issue of Cancer Cell, and was performed in mice genetically engineered to have breast cancer. When they induced anti-angiogenesis, they saw a 30 percent decrease in the volume of each tumor over 25 days. But the number of tumors that had metastasized to the lungs tumors tripled compared to untreated control mice.

Kalluri and his team performed a previous study in humans that found breast cancer patients with fewer cells called pericytes, which support the walls of veins, were less likely to survive their cancer. It turns out those are the cells damaged by some anti-angiogenesis drugs. By studying the mice they found that those pericytes are important because without them tumors become weak and leaky. And that causes cancer cells to launch survival mechanisms: the researchers found a fivefold increase in factors inside the pericyte-lacking cells that promote cell migration and growth.

In plainer terms, big tumors are less likely to spread, which is pretty disturbing. I've had several family members who died at the hands of cancer shortly after the "good news" that doctors had "shrunk the tumor!" Was that tumor shrinkage actually what killed them?

It's possible, Kalluri says. But it's important to note that the drugs used in the study, Gleevec and Sutent, a good at the job the FDA approved them for. It's when doctors decide to use cancer drugs "off-label" (the FDA approves drugs for specific uses, but they can't tell doctors how to use the drugs) indications that the treatment could be worse than the disease.

"If cancer drugs are used randomly against all kinds of cancer without thinking about all the biology of the tumor, it could lead to a poor prognosis," Kalluri told me.

The study isn't an indictment of all anti-angiogenic cancer drugs however. Avastin, the most popular cancer drug in the world, is also based on anti-angiogenesis, but doesn't target pericytes. Rather, it targets endothelial cells, which are on the inside of blood vessels, whereas pericytes line the outside. In November, the FDA revoked its approval for using Avastin to treat breast cancer against the pleas of patients and their families. But that decision was unrelated to Kalluri's study—the FDA simply found that the drug wasn't working all that well for breast cancer.

That said, Dr. Kalluri wasn't completely sure whether damaging endothelial cells might also cause metastasis. But it's important, he said, for doctors to remember that tumors contains lots of types of cells, and they're not all bad.

"Seventy to 80 percent of cells in a breast tumors are non-cancer cells," he said. "Are they all bad? Some of them there to protect us."

Update: Dr. Adam Brufsky, a professor of medicine at the University of Pittsburgh wrote to express concern that this post might lead cancer patients to refuse prescribed meds. As stated in the post: Gleevec and Sutent work very well for the diseases the FDA has approved them for (leukemia and gastrointestinal tumors). Says Dr. Brufsky: "Gleevec is used for chronic myelogenous leukemia and gastrointestinal stromal cell tumors, where it is used against the c-abl and c-kit oncogenes. It has changed the natural history of both diseases and saved many lives."